Oral cancer prediction by noninvasive genetic screening

Oral squamous cell carcinomas (OSCCs) develop in genetically altered epithelium in the mucosal lining, also coined as fields, which are mostly not visible but occasionally present as white oral leukoplakia (OL) lesions. We developed a noninvasive genetic assay using next-generation sequencing (NGS) on brushed cells to detect the presence of genetically altered fields, including those that are not macroscopically visible. The assay demonstrated high accuracy in OL patients when brush samples were compared with biopsies as gold standard. In a cohort of Fanconi anemia patients, detection of mutations in prospectively collected oral brushes predicted oral cancer also when visible abnormalities were absent. We further provide insight in the molecular landscape of OL with frequent changes of TP53, FAT1 and NOTCH1. NGS analysis of noninvasively collected samples offers a highly accurate method to detect genetically altered fields in the oral cavity, and predicts development of OSCC in high-risk individuals. Noninvasive genetic screening can be employed to screen high-risk populations for cancer and precancer, map the extension of OL lesions beyond what is visible, map the oral cavity for precancerous changes even when visible abnormalities are absent, test accuracy of promising imaging modalities, monitor interventions and determine genetic progression as well as the natural history of the disease in the human patient.     

Effectiveness,safety and quality of life of trifluridine/tipiracil in pretreated patients with metastatic colorectal cancer: Real-world data from the noninterventional TACTIC study in Germany

The prospective, multicenter, noninterventional TACTIC study assessed effectiveness and safety of trifluridine/tipiracil (FTD/TPI) in patients with metastatic colorectal cancer (mCRC) in a real-world setting in Germany, thus evaluating the external validity of the findings from the pivotal RECOURSE trial. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, and quality of life (QoL). Subgroups comprised patients with good (<3 metastatic sites at inclusion, ≥18 months from diagnosis of first metastasis to inclusion) or poor (remaining patients) prognostic characteristics (GPC/PPC). GPC without liver metastases was considered best prognostic characteristics (BPC). In total, 307 eligible patients (pretreated or not suitable for other available therapies) were treated with FTD/TPI. Overall, median [95%-CI] OS was 7.4 months [6.4-8.6], median PFS was 2.9 months [2.8-3.3]. In BPC (n = 65) and GPC (n = 176) compared to PPC (n = 124) subgroup, median OS (13.3 [9.1-17.6] vs 8.9 [7.6-9.8] vs 5.1 [4.4-7.0] months) and median PFS (4.0 [3.3-5.3] vs 3.4 [3.0-3.7] vs 2.6 [2.4-2.8] months) were longer. Patient-reported QoL, assessed by validated questionnaires (EQ-5D-5L, PRO-CTCAE), was stable throughout FTD/TPI treatment. Predominant FTD/TPI-related adverse events of grades 3 or 4 were neutropenia (13.0%), leukopenia (7.5%), and anemia (5.2%). Altogether, palliative FTD/TPI therapy in patients with pretreated mCRC was associated with prolonged survival, delayed progression, maintained health-related QoL, and manageable toxicity. Low metastatic burden and indolent disease were favorable prognostic factors for survival. TACTIC confirms the effectiveness and safety of FTD/TPI, highlighting its value in routine clinical practice.     

Detection of recombinant and endogenous mouse melatonin receptors by monoclonal antibodies targeting the C‐terminal domain

Melatonin receptors play important roles in the regulation of circadian and seasonal rhythms, sleep, retinal functions, the immune system, depression, and type 2 diabetes development. Melatonin receptors are approved drug targets for insomnia, non‐24‐hour sleep‐wake disorders, and major depressive disorders. In mammals, two melatonin receptors (MTRs) exist, MT₁ and MT₂, belonging to the G protein‐coupled receptor (GPCR) superfamily. Similar to most other GPCRs, reliable antibodies recognizing melatonin receptors proved to be difficult to obtain. Here, we describe the development of the first monoclonal antibodies (mABs) for mouse MT₁ and MT₂. Purified antibodies were extensively characterized for specific reactivity with mouse, rat, and human MT₁ and MT₂ by Western blot, immunoprecipitation, immunofluorescence, and proximity ligation assay. Several mABs were specific for either mouse MT₁ or MT₂. None of the mABs cross‐reacted with rat MTRs, and some were able to react with human MTRs. The specificity of the selected mABs was validated by immunofluorescence microscopy in three established locations (retina, suprachiasmatic nuclei, pituitary gland) for MTR expression in mice using MTR‐KO mice as control. MT₂ expression was not detected in mouse insulinoma MIN6 cells or pancreatic beta‐cells. Collectively, we report the first monoclonal antibodies recognizing recombinant and native mouse melatonin receptors that will be valuable tools for future studies.     

Schwann cells as underestimated,major players in human skin physiology and pathology

Schwann cells (SCs) have long been recognized for their ability to support repair and promote axon regeneration following injury to the peripheral nervous system. In response to nerve injury, they rapidly dedifferentiate into a precursor-like state, secrete an array of inflammatory mediators and growth factors, proliferate, undergo epithelial-to-mesenchymal-like transformation to facilitate migration, phagocytose cellular debris and remodel the extracellular environment to promote regeneration of axons through the site of injury. However, even though a cutaneous role for SCs is becoming increasingly recognized, we argue in this Viewpoint essay that the likely complex functions of SCs in skin physiology and pathology beyond skin sensation and nerve repair deserve more attention and systemic research than they have received so far. For example, SCs promote wound healing, disseminate infection in leprosy, support the growth of neurofibromas/schwannomas and facilitate/accelerate the growth and invasion of melanoma. Despite representing a major dermal cell population, comparatively little is still known about the role of SCs in other dermatoses. To quintessentially illustrate the opportunities that promise to arise from a new skin research focus on SCs, we focus on two dermatoses that are not traditionally associated with SCs, that is, psoriasis and atopic dermatitis (AD), since both show distinct SC changes along with continuous nerve fibre degeneration and regeneration, and an impact of denervation on skin lesions. Specifically, we critically discuss the hypothesis that repeated activation of the SC repair programme occurs in and contributes to psoriasis and AD and delineate experimental approaches how to probe this clinically relevant hypothesis.